Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease

信号肽肽酶样2b调节淀粉样蛋白生成途径并在阿尔茨海默氏病中表现出a β 依赖性表达

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aβ cascade. Exogenous Aβ42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aβ production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced upregulation of SPPL2b may enhance Aβ production in a vicious cycle, further aggravating Aβ pathology. Therefore, SPPL2b emerges as a potential anti-Aβ drug target.

阿尔茨海默氏病 (AD) 是由异常的淀粉样 β-肽 (a β) 水平驱动的多因素疾病。在这项研究中，我们调查了早老素样信号肽肽酶样2b (SPPL2b) 在AD病理生理学中的作用及其作为a β 级联中可药用靶标的潜力。外源性Aβ42影响人类细胞系和急性小鼠脑切片中的SPPL2b表达。在appnl-g-f敲入AD小鼠和人类死后AD大脑中评估SPPL2b及其AD相关底物BRI2。在appnl-g-f小鼠中观察到SPPL2b的早期高皮质表达，随后在晚期AD病理学中下调，这与突触丧失相关。为了理解病理生理学SPPL2b失调的后果，我们发现SPPL2b过表达显著增加APP切割，而遗传缺失减少APP切割和a β 产生。值得注意的是，与健康对照样品相比，死后AD大脑显示出更高水平的SPPL2b的BRI2底物。这些结果强烈支持SPPL2b参与AD病理学。早期a β 诱导的SPPL2b上调可能在恶性循环中增强a β 的产生，进一步加重a β 病理。因此，SPPL2b成为潜在的抗a β 药物靶标。

REF: Maccioni R, Travisan C, Badman J, et al. Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease. Prog Neurobiol. 2024;235:102585. doi:10.1016/j.pneurobio.2024.102585 PMID: 38367747

Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset of Alzheimer’s disease-related neuropathology

年轻的症状前APP/PS1小鼠的慢性诱发癫痫发作诱导5-羟色胺变化并加速阿尔茨海默病相关神经病理学的发作

Hyperexcitability is intimately linked to Alzheimer's disease (AD) pathology, but the precise timing and contributions of neuronal hyperexcitability to disease progression is unclear. Seizure induction in rodent AD models can uncover new therapeutic targets. Further, investigator-evoked seizures can directly establish how hyperexcitability and AD-associated risk factors influence neuropathological hallmarks and disease course at presymptomatic stages. Evoked convulsive seizures and neuronal hyperexcitability in pre-symptomatic APP/PS1 mice promoted premature mortality without pathological Aβ plaque deposition, whereas PSEN2-N141I mice were unaffected. Disruptions in serotonin pathway metabolism in APP/PS1 mice was associated with increased glial reactivity without Aβ plaque deposition, demonstrating that neuronal hyperexcitability in early AD causes pathological Aβ overexpression and worsens long-term outcomes through a serotonin-related mechanism.

过度兴奋与阿尔茨海默氏病 (AD) 病理密切相关，但神经元过度兴奋对疾病进展的确切时机和贡献尚不清楚。啮齿动物AD模型中的癫痫发作诱导可以发现新的治疗靶点。此外，研究者诱发的癫痫发作可以直接确定过度兴奋和AD相关的危险因素如何影响症状前阶段的神经病理学标志和疾病进程。在有症状前的APP/PS1小鼠中诱发的惊厥性癫痫发作和神经元过度兴奋促进了过早死亡，而没有病理性a β 斑块沉积，而PSEN2-N141I小鼠则不受影响。APP/PS1小鼠中5-羟色胺途径代谢的中断与没有a β 斑块沉积的神经胶质反应性增加有关，表明早期AD中的神经元过度兴奋会导致病理性a β 过度表达，并通过5-羟色胺相关机制使长期结果恶化。

REF: Del Pozo A, Knox KM, Lehmann LM, et al. Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset of Alzheimer's disease-related neuropathology. Prog Neurobiol. 2024;235:102591. doi:10.1016/j.pneurobio.2024.102591 PMID: 38484965 PMCID: PMC11015961

Dissecting gene expression networks in the developing hippocampus through the lens of NEIL3 depletion

通过NEIL3耗竭的晶状体解剖发育中的海马中的基因表达网络

Gene regulation in the hippocampus is fundamental for its development, synaptic plasticity, memory formation, and adaptability. Comparisons of gene expression among different developmental stages, distinct cell types, and specific experimental conditions have identified differentially expressed genes contributing to the organization and functionality of hippocampal circuits. The NEIL3 DNA glycosylase, one of the DNA repair enzymes, plays an important role in hippocampal maturation and neuron functionality by shaping transcription. While differential gene expression (DGE) analysis has identified key genes involved, broader gene expression patterns crucial for high-order hippocampal functions remain uncharted. By utilizing the weighted gene co-expression network analysis (WGCNA), we mapped gene expression networks in immature (p8-neonatal) and mature (3 m-adult) hippocampal circuits in wild-type and NEIL3-deficient mice. Our study unveiled intricate gene network structures underlying hippocampal maturation, delineated modules of co-expressed genes, and pinpointed highly interconnected hub genes specific to the maturity of hippocampal subregions. We investigated variations within distinct gene network modules following NEIL3 depletion, uncovering NEIL3-targeted hub genes that influence module connectivity and specificity. By integrating WGCNA with DGE, we delve deeper into the NEIL3-dependent molecular intricacies of hippocampal maturation. This study provides a comprehensive systems-level analysis for assessing the potential correlation between gene connectivity and functional connectivity within the hippocampal network, thus shaping hippocampal function throughout development.

海马中的基因调控是其发育，突触可塑性，记忆形成和适应性的基础。比较不同发育阶段，不同细胞类型和特定实验条件之间的基因表达，已经确定了有助于海马回路组织和功能的差异表达基因。Neil3dna糖基化酶是DNA修复酶之一，通过塑造转录在海马成熟和神经元功能中起重要作用。虽然差异基因表达 (DGE) 分析已经确定了涉及的关键基因，但对于高阶海马功能至关重要的更广泛的基因表达模式仍然未知。通过利用加权基因共表达网络分析 (WGCNA)，我们绘制了野生型和NEIL3-deficient小鼠未成熟 (p8-neonatal) 和成熟 (3 m成年) 海马回路中的基因表达网络。我们的研究揭示了海马成熟的复杂基因网络结构，描绘了共表达基因的模块，并确定了海马亚区成熟特有的高度互连的枢纽基因。我们研究了NEIL3耗尽后不同基因网络模块内的变异，揭示了影响模块连接性和特异性的NEIL3-targeted枢纽基因。通过将WGCNA与DGE整合，我们更深入地研究了海马成熟的NEIL3-dependent分子复杂性。这项研究提供了一个全面的系统级分析，用于评估海马网络中基因连通性和功能连通性之间的潜在相关性，从而在整个发育过程中塑造海马功能。

REF: Bugaj AM, Kunath N, Saasen VL, et al. Dissecting gene expression networks in the developing hippocampus through the lens of NEIL3 depletion. Prog Neurobiol. 2024;235:102599. doi:10.1016/j.pneurobio.2024.102599 PMID: 38522610

The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology

CXC趋化因子和受体信号轴在ALS病理生理中的多方面作用

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS. Findings in preclinical models implicate these signaling pathways in motor neuron toxicity and neuroprotection, while in ALS patients dysregulation of CXCLs/CXCRs has been shown at both central and peripheral levels. Immunological monitoring of CXC-ligands in ALS may allow tracking of disease progression, while pharmacological modulation of CXC-receptors provides a novel therapeutic strategy. A deeper understanding of the interplay between CXC-mediated neuroinflammation and ALS is crucial to advance research into treatments for this debilitating uncurable disorder.

肌萎缩侧索硬化 (ALS) 是一种迟发性运动神经元疾病，具有复杂的遗传基础，至今仍没有明确的病因。免疫系统相关功能障碍和神经炎症机制的多个交织层正在成为ALS发作和进展的重要决定因素。在这篇综述中，我们收集了越来越多的证据，这些证据表明四种主要的CXC趋化因子/同源受体信号轴 (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) 参与了ALS的病理生理。临床前模型中的发现暗示了这些信号通路在运动神经元毒性和神经保护中，而在ALS患者中，CXCLs/CXCRs的失调已在中枢和外周水平上显示。ALS中CXC-配体的免疫学监测可以允许追踪疾病进展，而CXC-受体的药理学调节提供了新的治疗策略。深入了解CXC介导的神经炎症与ALS之间的相互作用对于推进对这种使人衰弱的无法治愈的疾病的治疗研究至关重要。

REF: La Cognata V, Morello G, Guarnaccia M, Cavallaro S. The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology. Prog Neurobiol. 2024;235:102587. doi:10.1016/j.pneurobio.2024.102587 PMID: 38367748

The unconditioned fear response in vertebrates deficient in dystrophin

缺乏肌营养不良蛋白的脊椎动物的无条件恐惧反应

Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response to stressful/threat stimuli. Dystrophin-deficient animal models of DMD demonstrate enhanced stress reactivity that manifests as sustained periods of immobility. When the threat is repetitive or severe in nature, dystrophinopathy phenotypes can be exacerbated and even cause sudden death. Thus, it is apparent that enhanced sensitivity to stressful/threat stimuli in dystrophin-deficient vertebrates is a legitimate cause of concern for patients with DMD that could impact neurocognition and pathophysiology. This review discusses our current understanding of the mechanisms and consequences of the hypersensitive fear response in preclinical models of DMD and the potential challenges facing clinical translatability.

Duchenne肌营养不良 (DMD) 基因突变导致的肌营养不良蛋白丢失与广泛的神经认知合并症有关，包括对压力/威胁刺激的异常无条件恐惧反应。DMD的肌营养不良蛋白缺陷型动物模型显示出增强的应激反应性，表现为持续的不动期。当威胁在本质上是重复的或严重的时，肌营养不良蛋白病表型可能会加剧，甚至导致猝死。因此，很明显，在缺乏肌营养不良蛋白的脊椎动物中对压力/威胁刺激的敏感性增强是DMD患者可能影响神经认知和病理生理学的合理原因。这篇综述讨论了我们目前对DMD临床前模型中超敏恐惧反应的机制和后果的理解，以及临床可翻译性面临的潜在挑战。

REF: Gharibi S, Vaillend C, Lindsay A. The unconditioned fear response in vertebrates deficient in dystrophin. Prog Neurobiol. 2024;235:102590. doi:10.1016/j.pneurobio.2024.102590 PMID: 38484964

Optogenetic and chemogenetic approaches for modeling neurological disorders in vivo

用于体内神经系统疾病建模的光遗传学和化学遗传学方法

Animal models of human neurological disorders provide valuable experimental tools which enable us to study various aspects of disorder pathogeneses, ranging from structural abnormalities and disrupted metabolism and signaling to motor and mental deficits, and allow us to test novel therapies in preclinical studies. To be valid, these animal models should recapitulate complex pathological features at the molecular, cellular, tissue, and behavioral levels as closely as possible to those observed in human subjects. Pathological states resembling known human neurological disorders can be induced in animal species by toxins, genetic factors, lesioning, or exposure to extreme conditions. In recent years, novel animal models recapitulating neuropathologies in humans have been introduced. These animal models are based on synthetic biology approaches: opto- and chemogenetics. In this paper, we review recent opto- and chemogenetics-based animal models of human neurological disorders. These models allow for the creation of pathological states by disrupting specific processes at the cellular level. The artificial pathological states mimic a range of human neurological disorders, such as aging-related dementia, Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, and ataxias. Opto- and chemogenetics provide new opportunities unavailable with other animal models of human neurological disorders. These techniques enable researchers to induce neuropathological states varying in severity and ranging from acute to chronic. We also discuss future directions for the development and application of synthetic biology approaches for modeling neurological disorders.

人类神经系统疾病的动物模型提供了有价值的实验工具，使我们能够研究疾病发病机制的各个方面，从结构异常，新陈代谢和信号传导到运动和精神缺陷，并使我们能够在临床前研究中测试新疗法。为了有效，这些动物模型应该在分子、细胞、组织和行为水平上概括复杂的病理特征，尽可能接近在人类受试者中观察到的那些。在动物物种中，毒素，遗传因素，损伤或暴露于极端条件下可诱发类似于已知人类神经系统疾病的病理状态。近年来，已经引入了概括人类神经病理学的新型动物模型。这些动物模型基于合成生物学方法: 光遗传学和化学遗传学。在本文中，我们回顾了最近基于人类神经系统疾病的基于光遗传学和化学遗传学的动物模型。这些模型允许通过破坏细胞水平的特定过程来产生病理状态。人工病理状态模拟了一系列人类神经系统疾病，例如与衰老相关的痴呆症，阿尔茨海默氏病和帕金森氏病，肌萎缩性侧索硬化症，癫痫和共济失调。光遗传学和化学遗传学为人类神经系统疾病的其他动物模型提供了新的机会。这些技术使研究人员能够诱导严重程度不同的神经病理状态，从急性到慢性。我们还讨论了用于模拟神经系统疾病的合成生物学方法的开发和应用的未来方向。

REF: Krut' VG, Kalinichenko AL, Maltsev DI, et al. Optogenetic and chemogenetic approaches for modeling neurological disorders in vivo. Prog Neurobiol. 2024;235:102600. doi:10.1016/j.pneurobio.2024.102600 PMID: 38548126